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Description of key information

Dipropylene triamine (3,3'-iminodi(propylamine)) belongs to the structural class of polyamines. Absorption was demonstrated for the oral, dermal and inhalation route. Since the test substance is described as miscible in water in any ratio, a distribution through extracellular body fluids is likely. Metabolism is expected to occur via N-acetylation and deamination reactions. Urinary excretion of absorbed substance is considered as the predominate route of excretion. No bioaccumulation is expected.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

The main toxicokinetic properties of 3,3'-iminodi(propylamine) (CAS-No. 56-18-8) are assessed on the basis of its physico-chemical properties and with special regard to the results of the standard toxicity studies performed with this substance. Substance specific toxicokinetic or dermal absorption studies are not available.

 

 

1. Relevant physico-chemical properties of Dipropylene triamine

Molecular weight:

131.2193 g/mol

Physical state:

liquid at room temperature

Boiling point:

239°C (at 1013.3 hPa)

logPow:

-1.25 (at 25°C)

Water solubility:

miscible with water at all ratios

pKa:

pKa1 = 11.70 at 0°C, 10.70 at 30°C and 10.12 at 5 0°C

 

pKa2 = 10.77 at 0°C, 9.70 at 30°C and 9.19 at 50°C

 

pKa3 = 8.98 at 0°C, 8.02 at 30°C and 7.62 at 50°C

Vapour pressure:

1.263 Pa (at 20°C)

Hydrolysis:

Hydrolysis is not expected due to the absence of hydrolysable groups

Surface tension:

Based on chemical structure, no surface activity is to be expected

 

 

 

2. Absorption

Oral absorption

The molecular weight of the substance (below 200 g/mol) favours absorption after oral exposure as passage through the aqueous pores or transport through the epithelial barrier by the bulk passage of water is not restricted. In contrast, the following factors are more in favour of a limited oral absorption: A) It is generally thought that ionized substances do not readily pass biological membranes. Due to the high pKa values the amine groups of this compound are present almost exclusively in protonated (ionic) form at the usually neutral pH in the oral cavity and at the pH range present in the gastro-intestinal tract. B) The unlimited water solubility indicates that passive diffusion through membranes might be limited by the rate at which the substance partitions out of the gastrointestinal fluid.

Clinical signs and gross necropsy findings indicative of oral absorption were seen in the acute oral gavage study in rats (BASF AG, 1978). All tested doses caused irritating effects in the intestine, which generally enhances oral absorption due to damage of cell membranes. In the OECD 422 study (BASF SE, 2012) systemic toxicity occurred at dose levels which did not cause signs of irritation in the gastrointestinal tract. Thus, oral absorption occurs also at non-irritating substance concentrations.

In conclusion, high oral absorption is assumed to occur following administration of irritant substance concentrations, whereas a somewhat lower oral absorption can be assumed at non-irritant concentrations.

 

Dermal absorption

A high dermal absorption of the pure substance can be assumed because of its corrosive properties, which leads to the destruction of the skin barrier (as observed for instance in the rat acute dermal toxicity study (BASF AG, 1978) and in the skin irritation/corrosion study on rabbit skin (BASF AG, 1996)).

In contrast, dermal absorption at non-irritating substance concentrations is assumed to be very low. This is due to the fact the at the skin’s slightly acidic pH the substance will be ionized and thus, not be able to penetrate through the intact skin.

 

 

Inhalation absorption

Based on the vapor pressure less than 500 Pa (1.263 Pa at 20°C) and a boiling point above 150°C (239 °C) the test substance can be regarded as substance with low volatility (ECHA guidance on toxicokinetics, 2008). Exposure via inhalation is not likely. Nevertheless, if exposure to vapor or inhalable particles would occur, the water solubility indicates that significant portions of the substance may be retained in the mucus lining the tracheobronchiolar limiting the amount which deposits in the alveolar region.

The above assumptions are supported by the findings obtained in the acute inhalation toxicity studies. When the substance was applied as an aerosol at concentrations between 0.014 and 2.0 mg/L clinical signs and gross pathological findings consistent with an exposure of the whole respiratory tract were reported (BASF AG, 1979). In contrast, when rats were exposed to a vapor saturated atmosphere of the substance clinical signs indicative of upper airways effects were reported, but no effects in the lung were found at necropsy (BASF AG, 1978).

As already discussed for oral absorption, inhalation absorption is likely to occur directly across the respiratory tract epithelium by passive diffusion. Furthermore, irritant concentrations of the substance are thought to enhance inhalation absorption due to the induced cell membrane damage.

Overall, it is assumed that inhalation absorption occurs at a similar rate as oral absorption.

 

3. Distribution/Metabolism

At physiological pH the highly water soluble substance will be mostly ionized. Thus, diffusion across membranes might be limited and distribution throughout the body via the extracellular aqueous compartment seems likely. Distribution to the central nervous system and testis is likely to be restricted by the blood-brain and blood-testis barriers.

With respect to metabolic pathways in mammals, N-acetylation and oxidative deamination catalyzed by N-acetyltransferase/polyamine oxidase have been described for the structurally closely related compounds spermine and spermidine (Ferioli et al., 1996 and 1999; Seiler, 2004; Minois et al., 2011). The deamination reaction of both molecules leads finally to putrescine. These metabolic pathways can be also assumed for the present polyamine. Thus, N-acetyl-dipropylenetriamine, 1,3 -propylenediamine and monoacetylated propylenediamine are likely metabolites.

The conversion into metabolites that are more cytotoxic or more genotoxic than the parent substance was not noted when comparing in vitro test results with metabolic activation to test results without metabolic activation system (i.e. Ames-test +/- S9 (Zeiger et al., 1987), HPRT test (BASF SE, 2012) and in vitro MNT (BASF SE, 2012)). Based on this, an indication is not given that the formation of cytotoxic metabolites is likely.

 

4. Excretion

The relative low molecular weight (<200 g/mol) and excellent water solubility of 3,3'-iminodi(propylamine) and its expected metabolites lead to the conclusion that accumulation can be excluded and that urinary excretion will be the most relevant route of excretion. 

 

 

References

Ferioli ME, Sessa A, Tunici P, Pinotti O and Perin A (1996). Aging and polyamine acetylation in rat kidney. Biochim Biophys Acta 1317: 15-8.

Ferioli ME, Pinotti O, Pirona L (1999). Gender-related differences in polyamine oxidase activity in rat tissues. Amino Acids 17(2): 139-48.

Minois N, Carmona-Gutierrez D and Madeo F (2011). Polyamines in aging and disease. Aging 3:716-32.

Seiler N (2004). Catabolism of polyamines. Amino Acids26(3): 217 -3.